The ultimate objective of studies described here is to define viral and cell requirements for the entry of herpes simplex viruses types 1 and 2 (HSV- 1 and HSV-2) into cells of the genital tract and for spread of infection from the portal of entry to other tissues, particularly the nervous system. Mice inoculated via the vaginal route will provide an animal model of disease. This mouse model of infection and disease is likely to provide information relevant to human disease in part because human and mouse cell receptors for viral entry are homologues (encoded by evolutionarily related genes) and because many aspects of sexually transmitted disease caused by HSV in humans are similar to those observed in mice into inoculated via the vaginal route. Recently we cloned three different cDNAs encoding mouse receptors capable of mediating HSV entry into cells. All are homologous to known human receptors for HSV entry. We have also identified viral mutations that influence receptor usage or viral spread within the vaginal epithelium. The specific aims are to: 1) Determine whether the three mouse receptors cloned to date can account for the susceptibility of various cultured mouse cell types to HSV-1 and HSV-2 entry. 2) Identify viral mutations that alter receptor usage by HSV-1 and HSV-2. 3) Determine which mouse receptors are used by HSV-1 and HSV-2for entry into cells of the vaginal epithelium and for spread to other cell types including leukocytes and cells of the nervous system. The results of these studies will define molecular identify new approaches to protection of the vaginal epithelium and/for the nervous system from infection. In addition, they may identify strategies for the development of safer non-neurotropic vaccine strains of HSV.